In response to the RFA-RM-05-014, we plan to use both solid- and solution-phase strategies to synthesize several pilot-scale libraries to be submitted to NIH for subsequent distribution for various biological assays. Our aim is to prepare chemically pure, structurally diverse small-molecule compounds. These small-molecule compounds will be prepared by adaptation of published synthetic routes or, as appropriate, by development of novel synthetic strategies. Diversity-oriented synthesis (DOS) libraries will generally have ~100-200 members each with =90% purity of non-commercial small-molecules. Our plan is to prepare two types of libraries for each scaffold: (i) a small demo library to test the chemistry and validate the procedures, using the IRORI system for compound synthesis and tracking; (ii) a Trident- or IRORI-based library to deliver a focused library of compounds. The output of libraries (i) and (ii) will be combined, archived, and made available for biochemical evaluation. The dinitrodifluorobenzene-based scaffold will be prepared in larger number and quantity. Some of the solid-phase synthesis libraries will be generated with a built-in hydrophilic handle with site-specific functional groups so that these compounds can be subsequently tagged for specific assays while others will be prepared without any handle. Each compound will be analyzed by HPLC for purity and its identity confirmed by mass spectroscopy. If needed, FlashTube advanced flash chromatography will be used for compound purification. The NIH PubChem will be used for management of our various pilot libraries and we plan to set up a UC Davis Combinatorial Chemistry web site with links to PubChem. As required by the RFA, at least 10 mg of each library member will be archived and each will have =90% purity. [unreadable] [unreadable]